Skeletal development is normally characterized by marked expansion of cortical dimensions and increases in trabecular density during childhood and adolescence. Glucocorticoids (GC) are widely used for many pediatric disorders; however, GC suppresses osteoblast function and bone formation. GC-induced osteopenia may be exacerbated by the effects of the underlying disease, such as delayed growth and maturation, malnutrition, vitamin D deficiency and increased bone resorption by inflammatory cytokines. The combined effects of decreased bone formation and increased bone resorption may be particularly detrimental to the growing skeleton. The hypotheses of this study are: (a) GC therapy during growth results in impaired bone mineral accretion with decreased trabecular and cortical density, decreased cortical dimensions, and decreased bone strength; and (b) the inflammatory, nutritional and growth-related effects of the underlying disease contribute to abnormal bone mineral accretion during growth. Childhood nephrotic syndrome (NS) usually responds to GC and remains in remission as long as high-dose GC therapy is continued. In contrast, Crohn's disease (CD) is treated with GC, but is independently associated with poor growth and maturation, nutritional deficiencies and inflammation. Concurrent examination of the skeletal effects and disease characteristics of these two disorders will allow us to distinguish between GC- and disease-related effects. Unlike traditional densitometric measures of bone mass, peripheral quantitative computed tomography (pQCT) permits the discrete assessment of trabecular and cortical bone density and dimensions, and bone strength can be reliably estimated. The objective of this prospective cohort study is to use pQCT: (a) to identify determinants of trabecular and cortical bone development (density, dimensions and strength) among incident NS and CD patients prior to initiation of GC therapy; and (b) to determine the relationship between bone mineral accretion velocity (increases in density, dimensions and strength) and the pattern of GC exposure over a 12-month interval among 150 NS and 200 CD patients, adjusting for other growth- and disease-related determinants of bone mineralization. In healthy children, bone mass is highly correlated with growth and maturation; therefore, to understand the extent of bone deficits in children with NS and CD, these analyses will require a contemporary control group of similar age, gender, and ethnicity. The CHOP Normative Data Project (NDP) is an on-going initiative to collect cross-sectional measures of bone mineralization in healthy children. Our protocol will recruit 300 NDP participants to return for 6- and 12-month follow-up visits. The protocol will also examine levels of inflammatory cytokines and biomarkers of bone formation and resorption as predictors of bone mineral accretion during growth in NS and CD. Finally, the study will compare pQCT and DXA measures of bone mineral accretion in order to assess the utility of routine DXA in the assessment of GC effects in children. The accurate characterization of GC and disease effects on skeletal development is necessary to identify and evaluate targeted therapies to optimize skeletal architecture and peak bone mass in childhood.
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